Abstract One of the key obstacles to developing an effective HIV-1 vaccine is identifying adjuvants and immunogens that induce persistent HIV-1 envelope (Env) antigen specific antibody responses of high magnitude. Alum has been the choice of adjuvant for use in humans for almost a century now and also used in most HIV-1 vaccine clinical trials. However, Alum fails to induce persistent HIV-1 Env specific antibody responses of the appropriate quality (neutralizing activity or effector functions). Nanoparticulate adjuvants are known to enhance immune responses by rapidly draining and targeting key immune cells in lymph nodes. Our recently completed studies evaluating a novel TLR-7/8 ligand (3M-052) from 3M Pharmaceuticals by itself or in combination with a TLR-4 agonist GLA formulated in biodegradable synthetic polymer nanoparticles in rhesus macaques has for the first time successfully induced HIV-1 Env specific long-lived plasma cells (LLPCs) in the bone marrow. Robust and persistent antibody responses with binding, neutralizing and ADCC activity were also observed at high magnitude in addition to high frequencies of germinal center B cells and follicular T helper cells in draining lymph nodes. However, our polymer nanoparticles have faced challenges with manufacturability for use in humans. Hence, building on our proof of concept studies, in collaboration with the Infectious Disease Research Institute (IDRI) and 3M Pharmaceuticals, we now propose to a) evaluate a NanoAlum, novel clinically relevant Alum based nanoparticulate adjuvant with HIV-1 Env immunogens in combination with the 3M-052 molecule, b) establish new methodology that uses novel serum proteomics and BCR sequencing to rigorously investigate vaccine induced responses by defining key subsets of LLPCs in RMs and finally c) evaluate vaccine based protective efficacy upon virus challenge when combining sub-cutaneous vaccinations with such new adjuvants with intranasal vaccinations (IN) to improve mucosal immunity at genital mucosa.